TNFRSF1A (−135 T>C, rs767455) Polymorphism as a Predictor of Radiation Induced Oral Mucositis and Treatment Response in Locally Advanced Head and Neck Cancer Patients

INTRODUCTION: Head and neck squamous cell carcinoma (HNSCC) is the most common head and neck cancer in India, where intensity-modulated radiation therapy (IMRT) is the standard treatment. Despite therapeutic advances, variability in radiation response and toxicities persists. Genetic factors, including the TNFRSF1A (-135 T>C, rs767455) polymorphism, may influence susceptibility to oral mucositis, dermatitis, and treatment response, but remain insufficiently studied in Indian populations. Functional validation through serum TNF-α profiling and predictive modeling is also lacking. METHODS: ). Pre-treatment blood samples were analyzed for TNFRSF1A genotyping (PCR-RFLP) and serum TNF-α levels (ELISA). Oral mucositis and dermatitis were graded weekly using CTCAE v4.0, and treatment response was evaluated 90 days post-therapy by RECIST 1.1. Statistical analyses included Chi-square/Fisher's exact tests, odds ratios, Kruskal-Wallis ANOVA, and multivariate regression. A Random Forest model was applied for predictive evaluation. RESULTS: Genotype distribution was TT (52.0%), TC (38.0%), and CC (10.0%). Carriers of the C allele (TC/CC) had a significantly higher risk of severe mucositis (OR = 4.58, p = 0.010), while no association was observed with dermatitis. The TT genotype correlated with complete response (OR = 7.00, p = 0.002) and higher median serum TNF-α levels (13.28 pg/mL, p = 0.041). Multivariate analysis confirmed TNFRSF1A genotype as an independent predictor of mucositis and response, while age was protective against dermatitis. The Random Forest model achieved 60% accuracy in predicting treatment response. CONCLUSION: The TNFRSF1A (-135 T>C) polymorphism influences both toxicity and response in HNSCC, with the C allele predisposing to mucositis and the TT genotype predicting favorable outcomes. It represents a potential biomarker for personalized radiotherapy, meriting validation in larger cohorts.